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New Insight into How Genes Function

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Long segments of noncoding RNA are key to physically manipulating DNA in order to activate certain genes, say researchers at The Wistar Institute. These noncoding RNA-activators (ncRNA-a) have a crucial role in turning genes on and off during early embryonic development, the scientists say, and have also been connected with diseases including some cancers in adults.

Their findings also provide a plausible mechanism of how locations along chromosomes, known as enhancer elements, can influence the expression of genes located 5,000 to 100,000 base pairs of DNA away. According to their findings, ncRNA-a molecules bind to large protein complexes to form a loop of DNA, which then opens up the gene to the molecular machinery that transcribes DNA. “There is an abundance of evidence to indicate that enhancers are critical components of transcription during embryonic development and disease process,” says Ramin Shiekhattar, Ph.D., who led the team.

“Noncoding RNAs are probably one of the earliest molecules that determine spatial and temporal gene expression in a developing embryo,” he continues. “These enhancers can help turn genes on and off as a growing embryo would need, but as we have seen in other genetic mechanisms of embryonic development, they can lead to cancer if they are switched on inappropriately in adult cells.”

In recent years, scientists have found that not all transcribed RNA molecules become translated into proteins. In fact, studies have shown that large portions of the genome are transcribed into RNA that serve tasks other than functioning as blueprints for proteins. The Shiekhattar lab has since theorized on their role as enhancers of gene expression.

To discover how such enhancer-like RNAs function, Dr. Shiekhatter’s laboratory deleted candidate molecules with known roles in activating gene expression, and assessed if they were related to RNA-dependent activation. They found that depleting components of the protein complex known as Mediator specifically and potently diminished the ability of ncRNA-a to start the process of transcribing a gene into RNA.

Further, they found that these activating ncRNAs can attach to Mediator at multiple locations within the Mediator protein complex, and Mediator itself can interact with the enhancer element site on DNA that encodes these activating ncRNAs. Their results also determined how mutations in a protein that makes up the Mediator complex, called MED12, drastically diminishes Mediator’s ability to associate with activating ncRNAs.

Mutations in the MED12 protein are a marker for FG syndrome (also know as Opitz–Kaveggia syndrome), a rare genetic disorder that leads to abnormalities throughout the body and varying degrees of physical and neurological problems. “This clearly shows how activating ncRNAs can influence disease development, an idea that has been gaining evidence in the scientific literature,” Dr. Shiekhattar notes.

To confirm that ncRNA-a works with Mediator to form a loop in DNA, the researchers used a technique called chromosome conformation capture (3C) to gain a better understanding of the 3D structure of chromosomes. Their results show how Mediator gets a foothold on the portion of DNA that encodes the ncRNA-a, and twists the DNA to form a loop.

“The looping mechanism serves to physically bring together a distant enhancer element with the start site of the targeted gene, allowing Mediator to recruit the proteins responsible for reading the gene to the location,” Dr. Shiekhattar says. “It is at least one answer to how these classical enhancer elements function while being physically distant from their target genes.”

“Our DNA encodes thousands of these ncRNA-activators, each with a role in timing the expression of a specific gene. As we learn more about noncoding RNA, I believe we will have a profoundly better understanding of how our genes function,” says Dr. Shiekhattar, a Herbert Kean, M.D., family professor and senior author of the study. The study is published online in Nature.

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